Abstract 11567: The Transcription Cofactor Eya4 Regulates Age-dependent Adverse Cardiac Physiology
Introduction: We identified a mutation in the human transcription cofactor Eya4 (E193) to cause terminal heart failure preceded by sensorineural hearing loss. Eya proteins lack DNA-binding and nuclear translocation sequences and therefore must interact with real transcription factors, including Six family members. The cyclin-dependent kinase inhibitor p27kip1 (p27), one of the few known Eya-Six targets expressed in the heart has been shown to inhibit hypertrophic growth in adult cardiomyocytes. We hypothesize that Eya4/Six1 regulates targets relevant to sustain normal cardiac function via p27.
Methods and results: We examined the correlation of Eya4 and the mutant E193 overexpression upon p27 in permanent mammalian cell lines and primary cardiac myocytes. Westernblot analysis demonstrated that an overexpression of Eya4 led to a significant suppression of p27, whereas E193 had no effect on p27 levels; knockdown of Eya4 via siRNA exerted opposing effects. Promoter studies using a p27 promoter fragment including Six1 consensus sites revealed that the constitutive suppression of p27 by Eya4 could be released after targeting one of these consensus sites; E193 had no effect on p27 promoter activity. We generated transgenic mice with cardiac-specific overexpression of Eya4 and E193 to study the in vivo effect of Eya4 upon cardiac physiology. Eya4 transgenic mice developed hypertrophy under baseline conditions whereas E193 transgenic mice developed onset of cardiomyopathy similar to patients carrying the E193 mutation. HE-stainings showed ventricular hypertrophy or dilation of the LV associated with a thinning of the myocardial wall, respectively. PSR-stainings showed interstitial fibrosis of myocardial tissue in both transgenic mouse models, characteristic for cardiac disease.
Conclusion: In summary, we identified a mutation in Eya4 to cause DCM. Eya4/Six1 seems to suppress the expression of p27, an important inhibitor of the development of hypertrophy in postmitotic cardiomyocytes. Our transgenic mouse models with overexpression of Eya4 and the Eya4-mutant E193 support our hypothesis that Eya4 in complex with Six1 plays a critical role in maintaining cardiac physiology.
- © 2012 by American Heart Association, Inc.